Important Drug-Drug Interactions for the Addiction Psychiatrist.

The misuse of illicit substances, prescribed medications, and alcohol poses obvious health risks to afflicted individuals. When addressing these health risks, the overarching concerns generally relate to the direct effects that various substances can have on the functioning of multiple organ systems: cardiac, pulmonary, central nervous system, and others. What is not always evident, but potentially equally or even more dire, are the risks arising from drug-drug interactions involving illicit drugs and alcohol, whether with each other, or with prescribed medications. This review provides some basics that enable the reader to fruitfully approach the broad topic of drug-drug interactions.

Rapid resolution of psychotic symptoms in a patient with schizophrenia using allopurinol as an adjuvant: a case report.

CONTEXT: Despite multiple trials of different adjuvant therapies to an antipsychotic regimen, there have been few promising results. Allopurinol may be one promising adjunctive therapy based on three randomized controlled trials. OBJECTIVE: To determine whether adjuvant allopurinol would be beneficial to a patient already on multiple trials of antipsychotics with no improvement. RESULTS: Allopurinol was started with this particular patient who was on the inpatient unit for over three months with no prior improvement. Within two weeks of allopurinol adjuvant therapy, the patient showed significant improvement with regards to his positive and negative symptoms of schizophrenia (PANSS scores went from a score of 88 to a score of 41 two weeks later). CONCLUSIONS: Despite some limitations of this particular case report, it is possible that allopurinol can play an effective role as an adjuvant to antipsychotic regimens in reducing the symptoms of schizophrenia.

The pharmacokinetics of paliperidone versus risperidone.

BACKGROUND: Several new atypical antipsychotics have become available for use, but knowledge about their pharmacology may not be widespread. OBJECTIVE: This review aims to increase awareness and knowledge about risperidone (R) and paliperidone (9-hydroxyrisperidone [9-OHR]), their pharmacokinetics, and pharmacodynamics. METHOD: The authors present a review of the literature on R and 9-OHR. RESULTS: Oral R may be approximately twice as potent as oral 9-OHR. Levels of R and 9-OHR in R-treated patients may help clinicians prescribe 9-OHR. In R-treated patients, the R/9-OHR concentration ratio is an index of CYP2D6 activity; an inverted ratio (>1) indicates a CYP2D6 poor metabolizer (PM) or the presence of a powerful CYP2D6 inhibitor. The concentration-to-dose (C/D) ratio, where C includes R+9-OHR, is an index of total clearance from the body. A C/D ratio decreased by half is associated with CYP3A inducers or a lack of compliance, whereas an increased C/D ratio may indicate CYP2D6 PM phenotype, use of CYP2D6 and/or CYP3A4 inhibitors, or, possibly, renal insufficiency. In in-vitro studies, R and 9-OHR have similar receptor binding (except for blocking alpha(1)). 9-OHR may have less ability to enter the brain because of greater affinity for the transporter P-glycoprotein. The limited available paliperidone pharmacokinetic information suggests that there are four minor metabolic pathways. In contrast to R treatment, being a CYP2D6 PM may not be clinically relevant for paliperidone treatment. Information on paliperidone drug-drug interactions is limited. Renal excretion may be the major route of paliperidone elimination. CONCLUSION: Clinicians can use R/9-OHR and the C/D ratios to interpret plasma R levels and guide treatment.

Capacity to give surgical consent does not imply capacity to give anesthesia consent: implications for anesthesiologists.

There is precedent in medicine for recognizing and accepting intact decisional capacity and the subsequent ability to provide valid consent in one treatment domain, while simultaneously recognizing that the patient lacks decisional capacity in other domains. As such, obtaining consent for anesthesia for a surgical procedure is a separate entity from obtaining consent for the surgery itself. Anesthesia for surgery and the surgical procedure itself are separate treatment domains and as such require separate consents. Anesthesiologists should understand the independence of these functionally linked consent processes and be vigilant with respect to the informed consent process. The cases reported in this article show that capacity for surgical consent may be inadequate for consent to anesthesia because anesthesia involves more abstract concepts requiring a higher cognitive state than surgery, thus requiring a higher state of cognitive capacity for understanding.

Pharmacokinetic drug interactions of synthetic opiate analgesics.

Earlier reviews have covered pharmacokinetic drug interactions of natural and semi-synthetic opioid analgesics. This review will focus on the pharmacokinetic drug-drug interactions of methadone, propoxyphene, levomethadyl, meperidine, other phenylpiperidines (such as fentanyl), pentazocine, diphenoxylate, loperimide, and tramadol. The authors present an extensive review of the current literature. These drugs, with a few exceptions, are, at least partially, if not primarily, metabolized by the cytochrome P450 isoenzyme system (CYP) 3A4, and the action/interaction of these enzymes can have an effect on outcome. Therefore, these drugs are likely to produce drug-drug interactions when the CYP3A4 system is inhibited or induced. Knowledge of these drug-drug interactions is important because such interactions may decrease drug efficacy or result in adverse effects.

A double-blind trial of adjunctive allopurinol for schizophrenia.

OBJECTIVE: To investigate if adjunctive allopurinol reduces symptoms in schizophrenia outpatients with persistent symptoms despite adequate pharmacotherapy. METHOD: N=59 schizophrenia outpatients were randomly assigned to receive adjunctive allopurinol 300 mg bid or identical-looking placebo for 8 weeks after a 2-week placebo run-in. Symptoms were assessed biweekly. RESULTS: A total of n=51 patients completed the trial. Including all n=59 randomized patients, a total of 4 of 31 in the allopurinol group and 0 of 28 in the placebo group had at least a 20% reduction in total PANSS score at the final study visit (chi-square=3.88, p=.049). Among the n=51 completers, individuals in the allopurinol group rated themselves as more improved than did those in the placebo group (z=-2.24, p=.025). The allopurinol medication was well tolerated and there were not any adverse events attributed to the study medication. CONCLUSIONS: Allopurinol may be an effective adjunctive medication for some patients with persistent schizophrenia.

A preliminary attempt to personalize risperidone dosing using drug-drug interactions and genetics: part I.

BACKGROUND: Personalized prescription is described even in lay journals, but there has been no attempt to propose personalizing dosing for any specific psychiatric drug. OBJECTIVE: Any attempt to develop personalized dosing needs to be anchored in our understanding of the pharmacological response of each drug in each person's environment, particularly drug-drug interactions (DDIs) and how genetic make-up influences drug response. METHOD: Risperidone (R) is used as an example. R's pharmacologic response is reviewed in detail by focusing on our current knowledge of its pharmacodynamic and pharmacokinetic actions. The influences of the environment and genetics on these two actions are reviewed. RESULTS: R's antipsychotic action is probably mainly explained by the blocking of dopamine receptors, particularly D(2) receptors. There are polymorphic variations of this gene (DRD(2)), but it is not clear that they have clinical relevance in predicting adverse drug reactions (ADRs) or antipsychotic response. CONCLUSION: Previous exposure to antipsychotics increases the need for higher R dosing, but the mechanism for this tolerance is not well understood. Other brain receptors, such as other dopamine, serotonin, and adrenergic receptors may explain some of these ADRs. Some polymorphic variations in these receptors have been described, but they cannot yet be used to personalize R dosing.

Oral contraceptives.

Nearly 50 years ago, the introduction of Enovid (norethynodrel 10 microg and mestranol 150 microg), which provided convenient and reliable contraception, revolutionized birth control. Reports of interactions between oral contraceptives (OCs) and other drugs began to trickle into the literature. At first, these drug interactions appeared to be random and unrelated. Increased understanding of P450 enzymes and phase II reactions of sulfation and glucuronidation has permitted preliminary categorization and assessment of the clinical relevance of these drug interactions.

Clozapine case series.

Clozapine is not a drug that is ever used casually. Patients generally are afflicted with severe illnesses and have demonstrated treatment resistance and/or intolerance to other therapeutic options before clozapine is seriously considered. When the clinical stakes are this high, it is especially important that physicians gain an appreciation for the various drug-drug interactions that can significantly increase or decrease clozapine blood levels; such pharmacokinetic changes can derail clozapine treatment by producing clozapine toxicity or loss of antipsychotic efficacy, respectively. The authors present a case series of five drug-drug interactions involving clozapine, each of which illustrates different mechanisms by which the metabolism of clozapine can be altered. Exploring these cases should help clinicians anticipate and avoid these undesirable drug-drug interactions.

Gastrointestinal medications.

Medications to address gastrointestinal disorders are among the most commonly dispensed somatic medications. The authors examine proton pump inhibitors, H(2) blockers, 5-HT(3) receptor-antagonists, and a few other drugs that are used to address this domain of medical concerns. The metabolic pathways, interactions with the P-glycoprotein transporter, and capabilities of inhibiting or inducing metabolic enzymes are elucidated for each drug. Specific drug-drug interactions with each agent are also detailed, including both psychotropic and non-psychotropic agents. Also, the article explores how different genotypic variants for specific cytochrome P450 enzymes have an impact on the effectiveness and likelihood of drug-drug interactions relating to specific gastro-intestinal medications.

Unrecognized drug-drug interactions: a cause of intraoperative cardiac arrest?

Many physicians overlook, or are unaware of, most drug-drug interactions. In our patient, the local anesthetic used for an axillary block may have been the precipitating drug in a cascade of drug-drug interactions that resulted in a cardiac arrest. The combination of multiple preoperative drug-drug interactions prevented the return of a stable native cardiac rhythm for almost 24 h. The mechanisms of interactions of these frequently used drugs are described, and the reader is guided to sources that identify and simplify the understanding of potentially dangerous drug-drug interactions.

An overview of psychotropic drug-drug interactions.

The psychotropic drug-drug interactions most likely to be relevant to psychiatrists' practices are examined. The metabolism and the enzymatic and P-glycoprotein inhibition/induction profiles of all antidepressants, antipsychotics, and mood stabilizers are described; all clinically meaningful drug-drug interactions between agents in these psychotropic classes, as well as with frequently encountered nonpsychotropic agents, are detailed; and information on the pharmacokinetic/pharmacodynamic results, mechanisms, and clinical consequences of these interactions is presented. Although the range of drug-drug interactions involving psychotropic agents is large, it is a finite and manageable subset of the much larger domain of all possible drug-drug interactions. Sophisticated computer programs will ultimately provide the best means of avoiding drug-drug interactions. Until these programs are developed, the best defense against drug-drug interactions is awareness and focused attention to this issue.